CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression
CYP1B1 expression promotes the proangiogenic phenotype of endothelium through decreased intracellular oxidative stress and thrombospondin-2 expression
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DOI：
10.1182/blood-2008-03-145219
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发表时间：
2009-01-15
期刊：
影响因子：
20.3
通讯作者：
Sheibani, Nader
中科院分区：
文献类型：
--
作者：
Tang, Yixin;Scheef, Elizabeth A.;Sheibani, Nader
来自细胞氧合过程的活性物质在血管稳态和包括早产儿视网膜病变在内的许多疾病的发病机制中起重要作用。我们发现，CYP 1B 1缺陷（CYP 1B 1（-/-））小鼠在氧诱导的缺血性视网膜病变过程中未能引起新生血管反应。此外，从CYP 1B 1（-/-）小鼠制备的视网膜内皮细胞（EC）粘附性较低，迁移性较低，并且不能进行毛细血管形态发生。当氧气水平降低或加入抗氧化剂时，这些异常的细胞反应完全逆转。CYP 1B 1（-/-）EC表现出氧化应激增加，抗血管生成因子血小板反应蛋白-2（TSP 2）表达量增加。在CYP 1B 1（-/-）小鼠视网膜中观察到脂质过氧化和TSP 2增加，并通过给予抗氧化剂逆转。在CYP 1B 1（-/-）EC中重新表达CYP 1B 1导致TSP 2表达下调和毛细血管形态发生的恢复。在CYP 1B 1（-/-）EC中TSP 2敲低也恢复了毛细血管形态发生。因此，CYP 1B 1代谢调节细胞内氧化应激的细胞产物，这增强了EC迁移和毛细血管形态发生抑制剂TSP 2的产生。有证据表明，在体内视网膜内皮细胞发生类似的变化，以限制新血管形成。（血。2009; 113：744-754）
Reactive species derived from cell oxygenation processes play an important role in vascular homeostasis and the pathogenesis of many diseases including retinopathy of prematurity. We show that CYP1B1-deficient (CYP1B1(-/-)) mice fail to elicit a neovascular response during oxygen-induced ischemic retinopathy. In addition, the retinal endothelial cells (ECs) prepared from CYP1B1(-/-) mice are less adherent, less migratory, and fail to undergo capillary morphogenesis. These aberrant cellular responses were completely reversed when oxygen levels were lowered or an antioxidant added. CYP1B1(-/-) ECs exhibited increased oxidative stress and expressed increased amounts of the antiangiogenic factor thrombospondin-2 (TSP2). Increased lipid peroxidation and TSP2 were both observed in retinas from CYP1B1(-/-) mice and were reversed by administration of an antioxidant. Reexpression of CYP1B1 in CYP1B1(-/-) ECs resulted in down-regulation of TSP2 expression and restoration of capillary morphogenesis. A TSP2 knockdown in CYP1B1(-/-) ECs also restored capillary morphogenesis. Thus, CYP1B1 metabolizes cell products that modulate intracellular oxidative stress, which enhances production of TSP2, an inhibitor of EC migration and capillary morphogenesis. Evidence is presented that similar changes occur in retinal endothelium in vivo to limit neovascularization. (Blood. 2009; 113: 744-754)